Granulation process

ABSTRACT

A process for the manufacture of a corn starch granulate possessing resistance to enzymatic degradation upon oral administration, comprising the steps: a) granulating native corn starch by cautious mixing of a granulation fluid comprising methyl cellulose or ethyl cellulose as a binder, ethanol or water as a solvent, corn starch and a sweetener, b) subjecting the granulated material resulting from step a) to wet sieving; c) drying the granulate obtained in step b) at a temperature less than about 55° C. to avoid gelatinization of the corn starch; and d) sizing the dried granulate from step c) by dry sieving. A corn starch granulate and a corn starch granulate tablet also are provided.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a process for the manufacture of a cornstarch granulate possessing resistance to enzymatic degradation uponoral administration, to a corn starch granulate and to a corn starchgranulate tablet comprising said corn starch granulate.

BACKGROUND ART

Near normalization of blood glucose levels in diabetes is associatedwith around 50% less risk of nephropathy and retinopathy. However, theaim of normalizing the blood glucose levels is impeded by the risk ofinducing hypoglycemia—the Achilles heel of diabetes management. Severehypoglycemia is increased by 4-5 fold in patients with near-normal bloodglucose levels by such normalization. A majority of these episodes occurduring sleep. Nocturnal hypoglycemia represents a particularlythreatening condition to the patient. At daytime, it is possible for thepatient himself, or people in close proximity, to recognize and treatthe early autonomic warning symptoms. At nighttime, however, when thepatient is asleep the autonomic symptoms may not be enough to awaken thepatient. Therefore an initially mild hypoglycemic episode may easilyprogress into a severe episode at a time when external assistance maynot be available to the patient.

The causes of hypoglycemia may be recapitulated in a few keydeterminants. Available basal insulin formulations do not fully providethe required insulin supply at all times. Neither is food consumed in astandardized and consistent manner. Moreover, the nocturnal insulineffect reaches a peak around 3-5 a.m., a time when the dietary glucoseis absorbed and the risk of hypoglycemia is at its greatest. Loweringthe insulin dose is not a practical alternative because of the loss ofblood glucose control on the following day. In contrast, an oral therapythat provides a ‘timed’ nocturnal glucose delivery may balance anexcessive insulin effect without distorting blood glucose levels thefollowing day.

In exploring the options to optimize the nocturnal glucose deliverydifferent test-snacks have been tested. Normal snacks, such as bread ormilk, produce a peak glucose delivery around 1-1½ hours after ingestion.Such a snack provokes early hyperglycemia without protecting againsthypoglycemia after mid-night. A solution appears to be found in the useof particular starches characterized by a low rate of glucose delivery.Native corn starch has a peak glucose delivery at ˜4 hours. Corn starchis used to avert nocturnal hypoglycemia in young children with glycogenstorage disease. Corn starch has also been tested in type 1 diabeticchildren. The comparison with a normal snack is clearly in favour of thecorn starch regimen with regard to averting nocturnal hypoglycemia. Ithas been shown that corn starch consumption at bedtime leads to a 70%reduced number of hypoglycemic episodes at 3 a.m. in type 1 diabeticadults. Moreover, the regimen does not appear to compromise the glycemiccontrol during a 4-week period, despite the fact that it is added as asupplement.

Native corn starch granules are used as the carbohydrate source. Thegranules range from approximately 2-32 μm in size.

Native corn starch is an odourless fine particular crystalline powderwith a water content within 10-14%. The crystallinity can be observed ina polarised light microscope and particles, e.g. granules with acharacteristic dark cross are evident.

The particle size together with the amount of intact granules is animportant factor for the enzymatic degradation profile of native cornstarch.

Starch granules are mainly made up of two components, amylose andamylopectin. Amylose has a linear structure while amylopectin isbranched. Both amylose and amylopectin consist of α-(1,4)-linked glucoseresidues while amylopectin also has α-(1,6)-linked glucose residues.Starch granules are insoluble in cold water and swell in warm. Theswelling is reversible until the temperature reaches 55-65° C.

Degradation of starch is catalysed by α-amylase. From amylose, the endproducts are maltose (approx. 90%) together with glucose andmaltotriose. From amylopectin, the same end products are produced,together with branched oligosaccharides (α-dextrins). In man, α-amylaseis present in saliva and in the small intestine. During in-vitro andin-vivo conditions the digestibility of starch depends on the source ofstarch as well as on the pre-treatment.

SUMMARY OF THE INVENTION

The main object of the present invention is to provide a controlled,slow release of glucose from an ingestible corn starch product. Such acorn starch product is, in other words, upon intake capable to optimizethe nocturnal glucose delivery to provide a “time” effective prophylaxisfor nocturnal hypoglycemia to persons with diabetes.

Thus, it is an object of the invention to provide a process for themanufacture of such a corn starch product which will provide forcontrolled glucose delivery by its resistance to enzymatic degradationupon oral administration.

Another object of the invention is to provide a process which is adoptedto industrial scale manufacture of such a corn starch product.

Another object of the invention is to provide corn starch products whichwill provide for controlled glucose delivery by their resistance toenzymatic degradation upon oral administration.

Yet another object of the invention is to provide corn starch productspossessing the desired degradation profile in combination with agreeabletaste and texture.

Still another object of the invention is to provide a process for thepreparation of a corn starch product using mild operational conditionsso as to maintain the primary corn starch granules intact as they appearin native corn starch.

Another object of the invention is to provide a corn starch formulationwhich on intake gives a desired increase in blood glucose levels forabout 2 to 4 hours longer than would the native starch per se give, i.e.for a duration of up to about 6 to 8 hours.

For these and other objects which will be clear from the followingdisclosure the present invention provides for a process for themanufacture of a corn starch granulate possessing resistance toenzymatic degradation upon oral administration, comprising the steps:

-   -   a) granulating native corn starch by cautious mixing of a        granulation fluid comprising methyl cellulose or ethyl cellulose        as a binder, ethanol or water as a solvent, corn starch and a        sweetener;    -   b) subjecting the granulated material resulting from step a) to        wet sieving;    -   c) drying the granulate obtained in step b) at a temperature        less than about 55° C. to avoid gelatinization of the corn        starch; and    -   d) sizing the dried granulate from step c) by dry sieving.

The particle size of the granulate is crucial to achieve slow release ofglucose. The conditions during the steps of granulation and subsequentsieving and drying all influence the particle size of the granulate.Cautious mixing is a prerequisite for successful sizing of the granulateat the end of its manufacturing process. Said cautious mixing isobtainable by a mixing operation which, when performed in a Diosna 600liter granulator, is discontinued when a motor current of about 30 to 40A, preferably about 33 to 36 A, is reached. The motor currentcorresponds to the force that is necessary to turn the rotor per meterof rotor. This endpoint reflects the final particle size of thegranulate (see further below). Cautious mixing is also obtainable bymixing operations substantially equivalent to the one described above,but performed e.g. in another granulator.

To achieve a controlled, slow release of glucose the choice of binder isvery important. Several common binders are unsuitable for use in thisprocess. The most obvious example is pre-gelatinized starch, which is asource of quickly released glucose. Other common binders, e.g. gums andalginates, cause microbial damage and/or introduce less desirabletexture to the product. In the process of the present invention thebinder is selected from methyl cellulose and ethyl cellulose. The latterbinders contribute to a slow release of glucose while they do not haveany of the mentioned negative properties.

The preferred binder is ethyl cellulose. Ethyl cellulose is insoluble inwater and thus more resistant to dissolution in the gastro-intestinaltract. A more resistant binder acts as a better barrier to degradationand hence contributes to a slow release profile. Further, ethylcellulose is widely commercially available and a pharmacopeic substance.

To achieve a controlled, slow release of glucose the choice of sweeteneris also very important. Common sweeteners as glucose and sucrose areunsuitable as they contribute to a fast release of glucose. Preferredsweeteners, such as isomalt, fructose, xylitol and aspartame, do notdegrade to glucose.

The most preferred sweetener is isomalt, and optionally, aspartame.Isomalt is able to serve as a supplementary binder besides acting as asweetener.

Other features of the process according to the invention are given inthe appended claims.

The process according to the invention suitably involves a further stepof pressing the granulate into tablets each weighing about 1 to 10 g.Such a weight allows for administration of the daily suitable amount ofglucose in a reasonable number of tablets.

The mouthfeel of the tablet depends to a great extent on their hardness.More compressed tablets are more palatable, as the gritty properties ofthe starch granulate will be less evident in such tablets. Thecompression force exerted to press tablets may, however, cause damage tothe native starch granules and hence increase the release rate ofglucose. A combination of advantageous tablet properties is found whenthe tablets are pressed with a main compression force in the range ofabout 30 to 40 kN.

The present invention also relates to a corn starch granulate comprisingprimary corn starch granules as they appear in untreated native cornstarch, said primary granules being agglomerated, without degradationthereof, into larger secondary granules to form a granulate using abinder selected from methyl cellulose and ethyl cellulose.

It is preferred that corn starch is a major constituent in the granulesand that the binder is present in an amount of about 5 to 15% by weightbased on the weight of the granulate.

However, the binder need not be pre-dissolved but can be admixedtogether with the other components.

It is preferred that corn starch is a major constituent in the granulesand constitutes more than about half and preferably more than about ⅔ byweight of said granulate.

Such granulates preferably also comprise isomalt to assist ingranulation and to add taste to the granulate. Isomalt is normally notutilized as a carbohydrate source in humans and will not significantlycontribute with fast carbohydrates so as to compromise evening bloodglucose levels. Furthermore, isomalt is also a less digestiblecarbohydrate source for bacteria in the mouth so as to further reducethe risk for caries.

Preferably the isomalt is present in an amount of about 5 to 30% basedon the weight of the granulate.

The particle size of the primary starch granules and the secondarygranules of the granulate is crucial to achieve slow release of glucose.In general, larger particles contribute to slower release of glucose.

Thus, it is preferred that the primary granules have an average crossdimension of about 15 to 25 μm.

It is further preferred that the secondary granules have an averagecross dimension of about 0.3 to 1 mm. More specifically, to achieve thedesirable release profile it is preferred that at least 75% of thesecondary granules have an average cross dimension of at least 250 μm.However, particles<250 μm contribute in the formation of tablets of thegranulate and should thus not be fully avoided if the granulate is to beused for the manufacture of tablets.

When scaling up the granulation process it was extremely difficult toproduce a granulate giving the required release profile. Throughoptimization it was surprisingly found that the preferred particle sizeto give the desired release profile is >710 μm. Thus, more preferably 35to 80% of the secondary granules have a average cross dimension of atleast 710 μm.

Other features of the corn starch product according to the presentinvention are found in the appended claims. Such features involves theuse of carefully selected additives to improve the taste of thegranulate.

The fruit acid, such as malic acid, is used to stimulate the salivationduring ingestion to reduce the perception of a “dry compound”.Furthermore, aroma is used to improve taste; lemon scent is especiallywell tasting in combination with the basic taste and texture of theformulation.

Aspartame was surprisingly shown to mask the “chalkyness” of the cornstarch. Although not proved, it seems as though the perception of boththe “chalkyness” and the sweet sensation of aspartame occurs in thebrain at the same time, thus masking the chalky taste of corn starch.

The present invention also relates to a corn starch granulate tabletcomprising said corn starch granulate, said tablet having a crushingstrength of about 2 to 18 kp.

The mouthfeel of the tablet depends to a great extent on their hardness.Tablets having a high crushing strength are more palatable, as thegritty properties of the starch granulate will be less evident in suchtablets. The compression force exerted to press tablets may, however,cause damage to the native starch granules and hence increase therelease rate of glucose. A combination of advantageous tablet propertiesis found at a crushing strength in the range of about 2 to 18 kp.

The crushing strength is preferably in the range of about 8 to 14 kp,most preferably in the range of about 11 to 13 kp.

The weight of the tablet is preferably in the range of about 1 to 10 g.Such a weight allows for administration of the daily suitable amount ofglucose in a reasonable number of tablets.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be described more in detail in the followingby specific examples and with reference to the appended drawings. Theexamples are not intended to limit the scope of the invention.

FIG. 1 shows a diagram on the blood glucose variation as a function oftime comparing an embodiment of the corn starch product of the inventionand a control devoid of corn starch in accordance with the invention.See Specific Example 3

FIG. 2 shows the release profiles for different fractions of a cornstarch granulate. See Specific Example 4.

FIG. 3 shows the taste score given to corn starch granulate tablets ofdifferent crushing strengths by a taste panel. See Specific Example 5.

FIG. 4 shows the release profile of glucose for granulate tablets ofdifferent crushing strengths. See Specific Example 5.

THE PROCESS IN GENERAL

The production process for the manufacture of corn starch granulate inaccordance with the invention is generally a wet granulation process. Agranulation fluid consisting of binder dissolved in denaturated ornon-denaturated ethanol of 70-99.5% is produced. However, the binderneed not be pre-dissolved but can be admixed together with the othercomponents. The granulation fluid as obtained is added to a powderpremix consisting of native corn starch and a sweetener and blended in amixer or other means for mixing the constituents. The moist mixture iswet sieved or gently milled in an oscillating sieve or equivalentthereto. The wet mass obtained is dried to dryness at a temperaturebelow about 55° C. The dried mass is dry sieved or gently milled tobrake up larger lumps in an oscillating sieve or similar device. Thedried granulates are then mixed with colloidal silica dioxide in anordinary mixer, double cone mixer or similar apparatus. In a secondmixing step magnesium stearate is admixed. Then tablets are compacted togive a crushing strength of about 2-18 kp in an ordinary tablet press.

SPECIFIC EXAMPLE 1

Manufacture of Corn Starch Granulate

9.2 kg ethyl cellulose is dissolved in 28 kg ethanol (70-99.5%). 68.60kg native corn starch and 16.25 kg isomalt are dry mixed in a mixer.After this mixing the ethanol containing ethyl cellulose is slowly addedto the dry mass and mixing is continued until a uniformly wetted mass isobtained.

The wetted mass is then sized through a 1 to 2 mm screen or mill to givea wet granulate. This wet granulate is then dried on trays or in afluidised bed at a temperature of less than about 55° C. to dryness. Thedried granulate is then sized through a 1 to 2 mm screen or mill.

However, as previously indicated, the binder need not be pre-dissolvedbut can be admixed together with the other components.

Preparation of Corn Starch Tablets

The dried and sieved granulate obtained above is mixed with 1 kgcolloidal silica for 10 minutes. 0.5 kg magnesium stearate is then addedand mixing is carried out for about 2 minutes. The final mix obtained istransferred to the hopper of a tablet press equipped with Ø 15-25 mmpunches with bevelled edges. Tablets of about 2 to 10 g are pressed togive a crushing strength of from about 12-14 kp.

SPECIFIC EXAMPLE 2

Corn Starch Granulate

Corn starch granulate is manufactured as described in Example 1 abovecontaining the following constituents given as percentage by weight.Corn starch 72.9 Ethyl cellulose 9.7 Isomalt PF 15.1 Malic acid 0.6Aroma lemon (citro) 0.2 Aspartame 0.04Corn Starch Tablets

To a corn starch granulate having the composition given above Aerosil200 1.0 and Mg-stearate 0.5 percent by weight are added for the transferinto tablets. The tablets have a weight of between about 2 to 10 g.

In the product described above in Example 2 corn starch has theadvantage that it is an unsatisfactory carbohydrate source for thebacteria of the oral cavity thereby minimizing the risk for caries.Isomalt is added as an extra granulation component as well as sweetener.Isomalt is normally not utilized as a carbohydrate source in humans andwill not significantly contribute with fast carbohydrates so as tocompromise evening blood glucose levels. Furthermore, isomalt is also aless digestible carbohydrate source for bacteria in the mouth so as tofurther reduce the risk for caries.

The fruit acid, such as malic acid, is used to stimulate the salivationduring ingestion to reduce the perception of a “dry compound”.Furthermore, aroma is used to improve taste; lemon scent is especiallywell tasting in combination with the basic taste and texture of theformulation.

Aspartame was surprisingly shown to mask the “chalkyness” of the cornstarch. Although not proved, it seems as though the perception of boththe “chalkyness” and the sweet sensation of aspartame occurs in thebrain at the same time, thus masking the chalky taste of corn starch.

When tested in vivo, the corn starch product of the invention results ina blood glucose profile increasing linearly from about 45 minutes toabout 5 hours, where-after it stays at the same level for at least about2 more hours. This is totally unexpected when compared to the originalrelease profile of native corn starch, which has a “low hill shaped”release profile. It is also quite unexpected to observe that such smallamount of corn starch as 5-20 grams will secure the blood glucose levelsfor such a long period of time as about 7-8 hours.

SPECIFIC EXAMPLE 3

Clinical Test

The patient arrives in the laboratory in the morning in fasting stateand without having taken the regular morning insulin dose. For theestablishment of a base line the blood glucose level will be stabilizedat. 5.5 to 6.5 mmol per litre with the help of a slow i.e. infusion ofinsulin combined with a glucose infusion. The insulin is administratedby an infusion rate, aiming at giving a blood insulin concentration of15-20 mU/l. The glucose concentration will be locked by customary clamptechnique, where blood sugar is measured every 5^(th) minute for 1 hourand the glucose infusion rate is adjusted if necessary to give thedesired blood glucose concentration. Thereafter the control medicationis given and the glucose clamp is continued for 6 hours.

During the test, day blood samples are withdrawn every 10^(th) minuteduring the first 6 hours of the experiment for glucose determination,and also every 60^(th) minute for insulin determination.

The result of the clinical test is summarized in the diagram of FIG. 1.Herein the blood glucose level in mmol/l is plotted as a function oftime. Six tablets according to Specific Example 2 having a total weightof about 15 g and a total starch weight of about 10 g have been taken attime 0 and compared with a control not containing corn starch granulateaccording to the invention.

As is clear from the diagram, the blood glucose profile using thetablets of the present invention compared to the control is indeedsurprisingly different and results in a pronounced increase in bloodglucose level up to about 4-5 hours and then staying at the same levelat least about 2 hours more. The blood glucose profile obtained byexercising the present invention indeed constitutes a great improvementin regard to the diabetes problem and greatly facilitates the treatmentof diabetes with regard to the nocturnal hypoglycemia level inindividuals suffering from diabetes.

Moreover, the tablets of this invention possess the unexpected featureof giving a slow release of the glucose contents of the starch in spiteof the fact that the tablet is subjected to chewing.

SPECIFIC EXAMPLE 4

Granulate Particle Size

A corn starch granulate of the formulation in Table 1 was producedaccording to the general method described in Specific Example 1. Thegranules were sieved and collected in the fractions 0-180 μm, 180-710 μmand 710-1400 μm. The fractions were analysed for their release profilebased on enzymatic degradation. TABLE 1 Component Amount (g) Activesubstance Corn starch 3,643 Excipients Isomalt 754 Ethyl cellulose 485Malic acid 30 Flav P Lemon caps 11 Aspartame powder 2 Colloidal silicondioxide 50 Magnesium stearate 25 Total 5,000The release profiles of the fractions are shown in FIG. 2. The fractionsconsisting of the smallest granules (0-180 μm) resulted in highestabsorbance and thus fastest release. The fractions consisting of thelarger granules (180-710 μm and 710-1400 μm, respectively) resulted inlower absorbances and thus slower release profiles.

To achieve the desirable release profile, the particle size has now beenoptimized according to Table 2. The allowance of particles<250 μm isbased on their contribution to compressibility. TABLE 2 Particle size(μm) Weight (%) >250  75 >710 35-80 <2000 100

SPECIFIC EXAMPLE 5

Crushing Strength

Tablets with different crushing strengths in the range of from 2 to 18kp were prepared in lab scale from corn starch granulate according toSpecific Example 2. A taste panel of six persons, scoring the differenttablets on taste and texture judged the tablets. The results are shownin FIG. 3. The panel decided that the optimal crushing strength, from ataste/texture point of view, was approx. 16 kp.

When scaling up the tablet manufacture process to industrial scale andproducing tablets with a crushing strength of 16 to 18 kp, as desiredfrom a taste and texture perspective, the tablets did not show thedesired controlled release curve, but a considerably faster releaseprofile. Thus, it was surprisingly found that there was a reciprocalrelationship between the release profile and the crushing strength, i.e.the softer the tablet the slower the release profile. The results areshown in FIG. 4.

For this reason, it was decided to combine a high crushing strength witha sustained release profile, e.g. about 8 to 14 kp, preferably about 11to 13 kp.

1. A process for the manufacture of a corn starch granulate possessingresistance to enzymatic degradation upon oral administration, comprisingthe steps: a) granulating native corn starch by cautious mixing of agranulation fluid comprising methyl cellulose or ethyl cellulose as abinder, ethanol or water as a solvent, corn starch and a sweetener; b)subjecting the granulated material resulting from step a) to wetsieving; c) drying the granulate obtained in step b) at a temperatureless than about 55° C. to avoid gelatinization of the corn starch; andd) sizing the dried granulate from step c) by dry sieving.
 2. A processaccording to claim 1, wherein said binder is ethyl cellulose.
 3. Aprocess according to claim 1, wherein the sweetener is selected fromisomalt, fructose, xylitol, and aspartame.
 4. A process according to anyclaim 1, wherein said binder is admixed into ethanol or is admixedtogether with the other components.
 5. A process according to claim 3,wherein said sweetener is selected from the group consisting of isomalt,and a combination of isomalt and aspartame.
 6. A process according toclaim 1, comprising the steps: a) granulating native corn starch bycautious mixing of a granulating fluid comprising ethyl cellulose,preferably dissolved in ethanol and a premix of corn starch and isomaltas a sweetener; b) subjecting the granulated material resulting fromstep a) to wet sieving by sizing through a screen or mill within therange about 1 to 3 mm; c) drying the wet granulate obtained from step b)at a temperature of less than about 55° C.; and d) sizing the driedgranulate from step c) on a screen or mill within the range about 1 to 2mm.
 7. A process according to claim 1, wherein said cautious mixing isobtainable by a mixing operation which, when performed in a Diosna 600liter granulator, is discontinued when a motor current of about 30 to 40A is reached.
 8. A process according to claim 1, comprising the furtherstep of pressing the granulate into tablets each weighing 1 to 10 g. 9.A process according to claim 8, wherein said further step is comprisedby mixing the granulate with colloidal silica for improving flow andwith magnesium stearate as a lubricant before pressing the granulateinto tablets.
 10. A process according to claim 8, wherein the tabletsare pressed to give a crushing strength of about 2 to 18 kp.
 11. Aprocess according to claim 8, wherein the tablets are pressed with amain compression force of about 30 to 40 kN.
 12. Corn starch granulateobtained by the process of claim
 1. 13. Corn starch granulate comprisingprimary corn starch granules as they appear in untreated native cornstarch, said primary granules being agglomerated, without degradationthereof, into larger secondary granules to form a granulate using abinder selected from methyl cellulose and ethyl cellulose.
 14. Granulateaccording to claim 13, wherein the binder is ethyl cellulose. 15.Granulate according to claim 13, wherein corn starch is a majorconstituent, and wherein the binder is present in an amount of about 5to 15% by weight based on the weight of the granulate.
 16. Granulateaccording to claim 15, wherein corn starch constitutes more than abouthalf by weight of said granulate.
 17. Granulate according to claim 13,further comprising isomalt to assist in granulation and to add taste tothe granules.
 18. Granulate according to claim 17, wherein isomalt ispresent in an amount of about 5 to 30% by weight based on the weight ofthe granulate.
 19. Granulate according to claim 13, wherein a majorityof the primary granules have an average cross dimension of about 15 to25 μm.
 20. Granulate according to claim 13, wherein a majority of thesecondary granules have an average cross dimension of about 0.3 to 1 mm.21. Granulate according to claim 13, wherein at least 75% of thesecondary granules have an average cross dimension of at least 250 μm.22. Granulate according to claim 20, wherein 35 to 80% of the secondarygranules have an average cross dimension of at least 710 μm. 23.Granulate according to claim 13, further comprising aspartame to furtheradd to the taste of the granulate.
 24. Granulate according to claim 23,wherein aspartame is present in an amount of about 0.01 to 0.1% byweight based on the weight of the granulate.
 25. Granulate according toclaim 13, further comprising a fruit acid to add flavour to thegranulate.
 26. Granulate according to claim 25, wherein said fruit acidis selected from the group consisting of malic acid, tartaric acid, andcitric acid.
 27. Granulate according to claim 25, wherein said acid ispresent in an amount of about 0.1 to 1.5% by weight based on the weightof the granulate.
 28. Granulate according to claim 13, furthercomprising an aroma substance.
 29. Granulate according to claim 28,wherein said aroma substance is of citrus origin.
 30. Granulateaccording to claim 28, wherein said aroma substance is present in anamount of about 0.1 to 1.0% by weight based on the weight of thegranulate.
 31. Corn starch granulate tablet obtained by the process ofclaim
 8. 32. Corn starch granulate tablet comprising a corn starchgranulate according to claim 13, said tablet having a crushing strengthof about 2 to 18 kp.
 33. Tablet according to claim 32, said tablethaving a crushing strength of about 8 to 14 kp.
 34. Tablet according toclaim 33, said tablet having a crushing strength of about 11 to 13 kp.35. Tablet according to claim 32, said tablet having a weight of about 1to 10 g.
 36. A process according to claim 2, wherein the sweetener isselected from isomalt, fructose, xylitol, and aspartame.
 37. A processaccording to claim 4, wherein said sweetener is selected from the groupconsisting of isomalt, and a combination of isomalt and aspartame.
 38. Aprocess according to claim 1, wherein said cautious mixing is obtainableby a mixing operation which, when performed in a Diosna 600 litergranulator, is discontinued when a motor current of about 33 to 36 A isreached.
 39. A process according to claim 9, wherein the tablets arepressed to give a crushing strength of about 2 to 18 kp.
 40. Granulateaccording to claim 14, wherein corn starch is a major constituent, andwherein the binder is present in an amount of about 5 to 15% by weightbased on the weight of the granulate.
 41. Granulate according to claim15, wherein corn starch constitutes more than about ⅔ by weight of saidgranulate.
 42. Granulate according to claim 21, wherein 35 to 80% of thesecondary granules have an average cross dimension of at least 710 μm.43. Granulate according to claim 26, wherein said acid is present in anamount of about 0.1 to 1.5% by weight based on the weight of thegranulate.
 44. Granulate according to claim 29, wherein said aromasubstance is present in an amount of about 0.1 to 1.0% by weight basedon the weight of the granulate.
 45. Tablet according to claim 33, saidtablet having a weight of about 1 to 10 g.
 46. Tablet according to claim34, said tablet having a weight of about 1 to 10 g.